PT87793B - A process for the preparation of aminopropanol derivatives of 3- (3-hydroxyphenyl) -1-propanone compounds and pharmaceutical compositions containing them - Google Patents

Abstract

Aminopropanol derivatives of 3-(3-hydroxyphenyl)-1-propanone of the formula I <IMAGE> and their acid addition salts.-

Description

DESCRIPTION OF THE INVENTION

Background of the Invention Invention relates to the process of preparing new aminopropanol derivatives of 3- (3-hydroxyphenyl) -1-propanone compounds of formula I and their physiologically acceptable acid addition salts.

German Patent l \ i ^s 2,001,431 discloses 2- (2'-hydroxy-3'-alquilaminopropoxi) yO-phenyl-Propiophenones of formula

and its acid addition salts. Although these compounds and their salts constitute pharmaceutical products, only the n-propylamino compound (propafenone) exhibits anti-arrhythmic activity.

EP-A-0 074 014 describes 2 -_ / 2 ¹ -hydroxy-3 ¹ - (1,1-dimethylpropylamino) -propoxy _ / - y3-phenyl 1-propiophenone (djprafsna na) and its addition salts of acid. Diprafenone is an ant

-Micro arrit.

EP-A-0 075 207 describes aminopropanol derivatives of the general formula

and its physiologically acceptable acid addition salts. Typical examples for R ^-R ^ include hydrogen atoms or alkyl groups and n is 1, 2 or 3. These compounds are pharmaceuticals.

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-5X

Summary of the Invention

An object of the present invention is to provide new aminopropanol derivatives of the 3- (3-hydroxyphenyl) -1-propanone compounds of formula I and their acid addition salts fi. syologically acceptable which are distinguished by a substantially improved antiarrhythmic activity compared to that of propafenone, without showing a corresponding increase in toxicity, it is another object of the invention to provide a process for the preparation of these compounds and their acid addition salts . Finally and an objective of the

It is an invention to provide pharmaceutical compositions for the treatment of heart rhythm disorders, containing those compounds or their physiologically acceptable acid addition salts.

Detailed Description of the Invention

The invention relates to new aminopropanol derivatives of 3- (3-hydroxyphenyl) -1-propanone compounds of general formula I

OH and its acid addition salts, and the process of preparing them. The invention also relates to pharmaceutical compositions containing a compound of formula I or a χ

its acid addition salt, preferably a physiologically acceptable acid addition salt.

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-6 '1 2

In general formula I, R and R are the same or different

X X and signify hydrogen atoms, alkyl, cycloalkyl, alkenyl, alkynyl, or hydroxyalkyl groups, with up to 6 carbon atoms each, alkoxyalkyl, alkylthioalkyl groups. lo or dialkylaminoalkyl, with up to 9 carbon atoms each, or phenylalkyl or phenoxyalkyl groups, having up to 6 carbon atoms in the alkyl portion, the phenyl group being optionally substituted by an alkyl or alkoxy group with, '' 1 2 respectively, up to 3 carbon bonds, or R and R form together with the nitrogen atom that connects them, a saturated heterocyclic ring, with 5 to 7 members, which can be optionally substituted by one or two phenyl and / or hiZ XX groups droxy and contain an oxygen or nitrogen atom in the ring as

X X is another heteroatom, with an additional nitrogen atom optionally substituted by an alkyl group having 1 to 3 carbon atoms, or by a phenyl group. R represents a hydrogen atom, an alkyl group with up to 3 carbon atoms,

XX X is a fluorine, chlorine or bromine atom, a hydroxyl group or al '. '. 4 coxy with up to 6 carbon atoms. R represents an atom of

X XX hydrogen, an alkyl group with up to 3 carbon atoms, an

X X X the atom of fluorine, chlorine or bromine, a hydroxyl group or an alkoxy group with up to 6 carbon atoms, or R with the phenyl group attached to it, forms part of a ring aromatic system having up to 18 carbon atoms. The letter n represents an integer from 1 to 5.

2 x

Compounds in which NR R and a tert-pentylamino, n-propylamino, 1,1-dimethylpropylamino, morpholino, isopropylamino, tert-butylamino, pyrrolidine, piperidine or cyclohexylamino group, r 3 * * are preferred are the residue R hydrogen, or a methyl, methoxy or hydroxy group,.

R is hydrogen or a methyl, methoxy or hydroxy group, or together with the phenyl group attached to them and a 1-naphthyl group, a 2-naphthyl group or a 3-phenanthrenyl group, and π has va67 864

X 602ΡΤ

-7lor 1, 2 or 3.

12 '

Especially preferred are compounds in which NR R and a tert-pentylamino, n-propylamino, isopropylamino, tert-butylamine, piperidine or cyclohexylamino group, the R and hydrogen residue or a methoxy group in position 4, '

R is a methyl or methoxy group or together with the phenyl group attached to it and a 2-naphthyl group and does not have a value of 1, 2 or 3.

The most preferred compounds are 1- (3,4,5-trimethoxyphenyl) -3- / 3 '- (2-hydroxy-3-tert-pentylaminopropoxy) phenyl _ / - 1-propanone hydrochloride, (Example 8). 1- (2,4,6-trimethylphenyl) -3- / 3 '- (2-hydroxy-3-tert-butylamino-propoxy) phenyl _ / - 1-propanone hydrochloride, (Example 17). 1- (3,4-dimethoxyphenyl) -3- / 3 '- (2-hydroxy-3-isopropylaminopropoxy) -4'-methoxyphenyl _ / - 1-propanone hydrochloride (Example 23). 1- (3,4,5-trimethoxyphenyl) -3- / 3 '- (2-hydroxy-3-cyclohexylamino-propoxy) -4'-methoxyphenyl _ / - 1-propanone hydrochloride (Example 32).

1- (2-naphthyl) -3- / 3 '- (2-hydroxy-3-n-propylaminopropoxy) -4'-methoxyphenyl _ / - 1-propanone hydrochloride (Example 48).

The invention also relates to a process of preparing compounds of formula I and their acid addition salts which is characterized by the reaction of a phenolic ether of formula II.

R ⁴ n

with an amine of general formula III

HNR ¹ R ² (III)

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-8 having R, R, R, R and the meaning given above.

5e suitable, the resulting compound of formula I can be converted with acid to an acid addition salt. The reaction can, for example, follow the method described in Paten. European 0 074 014.

The reaction is carried out at temperatures ranging from 10- to 120 ° C, that is, at room temperature or at higher temperatures, preferably at temperatures ranging from 50- to 12D ^S C, at atmospheric pressure, or in a closed pressure vessel. elevated.

The starting compounds of formulas II and III can be reacted without diluents or solvents. However, the reaction z z.

and preferably carried out in the presence of an inert diluent or solvent, such as lower alcohol having 1 to 4 carbon atoms such as, for example, methanol, ethanol or propanol, preferably isopropanol or ethanol, a dialkyl ether, saturated, lower, dialkylglycolic ethers or cyclic ethers, such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, a benzene zenocarbon, such as benzene itself or an alkylbenzene, in particular toluene or xylene or an aliphatic hydrocarbon such as hexane, heptane or octane, dimethylsulfoxide or in the presence of water or mixtures of the mentioned solvents.

When used in excess, the amine of general formula III can also be a suitable diluent or solvent.

The completion of the reaction depends on the temperature of z

reaction and is usually achieved in 2 to 15 hours. The reaction product can be obtained in a conventional manner, for example, by filtration or distillation of the diluent from the reaction mixture. □ compound obtained and purified in the usual way, for example, by recrystallization from a solvent, conversion to a cu acid addition salt by column chromatography.

phenyl ether of general formula II can be obtained

-9with formu67 864

X 6D2PT by alkylation of 3-hydroxy - / »- phenylpropiophenone la geral IV

(IV) with an epihalohydrin. R, R and n have the previous meaning. Examples of epihalohydrins are epichlorohydrin, epibromohydrin and epiiodohydrin.

The reaction of the compound of formula IV, for the preparation of the starting compounds of formula II, is conveniently carried out at temperatures ranging from 0-C to 120 ² C at normal pressure, or in a closed vessel, at high pressure. Suitable solvents or diluents are a lower aliphatic ketone, such as acetone, methyl ethyl ketone or methyl isobutylene, a lower alcohol, have 1 to 5 carbon atoms, such as methanol, ethanol, propanol or butanol, / umeter, cyclical or

Z Z Z aliphatic, lower, such as diethyl ether, tetrahydrofuran or dioxane, a dialkylformamide such as dimethylformam. mide or diethylformamide or dimethylsulfoxide or hexamethylphosphoric acid triamide, or an excess amount of an alkylating agent.

The reactions are preferably carried out in the presence of a base as an acid-binding agent. Suitable bases are alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkali metal hydrides or alkali metal alcoholates, in particular, sodium and potassium oxides, basic oxides such as aluminum oxide or oxide calcium, organic tertiary bases, such as pyridine, lower trialkylamines, such as trimethylamine or triethylamine, or piperidine. The bases

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10 can be used in catalytic or stoichiometric quantities. slightly in excess of the alkylating agent used.

3-hydroxy-enylpropiophenone is, preferably, area. mixed with epichlorohydrin or epibromohydrin in a polar, aprotic solvent, in particular in dimethylsulfoxide, at temperatures ranging from 0 ^s to 50 ^and C, in the presence of at least one mole of equivalent base, in particular sodium hydride, ba. based on the alkylating agent.

starting compound of general formula IV, ie the

3-hydroxy-y5-propiophenone and its preparation are known.

compound of formula I obtained according to the invention and optionally converted to an acid addition salt, pre. preferably in a physiologically acceptable acid salt. Physiologically acceptable, organic and inorganic acids, which are usual, are, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic acid and benzoic acid. Other suitable acids are described in Fortschritte der Arzneimittel-forschung, vol. 10, pp. 224-225, Birkhaeuser editors, Basle and Stuttgart, 1966 and Journal of Pharmaceutical Sciences, vol. 66, pp. 1-5 (1977). Α hydrochloric acid is preferred.

Acid addition salts are usually obtained in the conventional manner, by mixing the free base or its solutions with the corresponding acid or its solutions, in an organic solvent, for example, a lower alcohol such as methanol, ethanol, n-propanol or isopropanol , or a lower ketone such as methyl ethyl ketone or methyl isobutyl ketone, or an ether such as diethyl ether, tetrahydrofuran or dioxane. Aforementioned solvent mixtures can also be used to improve the deposition of crystals. Furthermore, pharmaceutically acceptable aqueous solutions of acid addition salts of compounds of formula I can be prepared in an aqueous solution

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- deal with acid.

cfc acid

The addition salts / of the compound of formula I can be converted to free bases in a manner known per se, for example, with alkalis or ion exchangers. Z can be obtained

other salts from the free base by reaction with organic or inorganic acids, in particular those which are suitable for the formation of therapeutically useful salts. These and other salts of the new compound, such as picrate, can they *>

The purification of the free base itself, in which the z z free base is converted into a salt, which is separated, and the base is released again from the salt.

the present invention also relates to pharmaceutical compositions

The maceuticas for oral, rectal, intravenous or intramuscular application, which in addition to the traditional haA z carriers and diluents, contain the compound of formula I, or an acid addition salt thereof, as an active ingredient. It also refers to the use of the new compound and its physiologically acceptable salts in the treatment of heart rhythm disorders.

The pharmaceutical compositions of the invention are prepared in a conventional manner with conventional, solid or liquid carriers or diluents and conventional pharmaceutical adjuvants, in a suitable dosage form, according to the desired application form. Preferred preparations are compositions in the form of a dosage unit for

Oral application. Such dosage forms are, for example, tablets, coated tablets, dragees, capsules, pills, powders, solutions or suspensions or deposit preparations.

z z

Parenteral preparations, such as solutions for injection, are of course also suitable. Another form of pharmaceuticals to be mentioned is, for example, the suppository.

The corresponding tablets can be obtained, for example, by mixing the active ingredient with known auxiliaries or for example with inert diluents such as dex. trose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, agen

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-12 disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or agents to achieve a deposit effect such as carboxyclimethylene, carboxymethylcellulose, acetate-phthalate cellulose or poly (vinyl acetate). The tablets may comprise several layers.

The dragees can be correspondingly prepared by coating cores which have been prepared analogously to the tablets, with compositions commonly used in the coating of dragees such as polyvinylpyrrolidone or zum gum, arabic gum, talc, titanium dioxide or sugar. The skin of the dragee may also consist of several layers in which various auxiliary agents mentioned above can be used in relation to the tablets.

Solutions or suspensions containing the ingredient acti. The invention may further contain flavoring agents such as saccharin, cyclamate or sugar and, for example, flavoring agents such as vanillin or orange extract. In addition, they may contain auxiliary suspending agents such as sodium carboxymethylcellulose or preservatives such as p-hydroxybenzoates. Capsules containing the active ingredient can, for example, be prepared by mixing the active ingredient with an inert carrier such as lactose or sorbitol, and then be encapsulated in gelatin capsules.

Suitable suppositories can be prepared, for example, by mixing the active ingredient with appropriate carriers, such as with neutral fats or polyethylene glycol or its derivatives.

In humans, the single dose is 0.5-5 mg / kg for oral administration, 0.05-2 mg / kg for intravenous administration, 0.1-3 mg / kg for intramuscular administration,

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-13 from 0.5-10 mg / kg for rectal administration.

In particular, the anti-arrhythmic and yes-pathogenic properties of the compounds of the invention and their addition salts. of physiologically acceptable acids, makes them especially suitable for pharmacotherapy of changes in heart rhythm, treatment of coronary heart disease and sudden death due to heart disease. The antiarrhythmic efficacy of the compounds of the invention has been confirmed both by studies electrophysiological effects on the Purkinje fibers of the dog food as with the aid of ventricular tachycardia in dogs, induced by ouabain.

In tables (I) and (II) the compounds of the invention are compared with propafenone (A).

effect on the contraction force of the heart was tested on the papillary muscle of guinea pigs. Studies are carried out

He r hemodynamics in both healthy and acute dogs. An important criterion in Table (I) that follows is the safety factor (SF) that is calculated from the relation enX X between the anti-arrhythmic efficiency, the negative inotropism and the efficiency specifically higher at higher frequencies, according to the formula: speed factor of Vmax x (C20 CF / / C20 Vmax). As a comparison, it is observed that the propafenone and flecainide anti-arrhythmic drugs currently more

Λ used have an S.F. of 1.5 and 1.7 respectively.

As a supplementary criterion, the prematurity factor was established. This characterizes the desired effectiveness of the compounds of the invention on premature extrasystoles.

great anti-arrhythmic effect is not accompanied by a significant increase in toxicity compared to propafenone (A) as can be seen by comparing the LD b U values in rats and mice, which are summarized in the table. la II.

864 X 602ΡΤ

-14TABELA I

Example No. C20 CF (/ η C20 Vmax (jfcM) Speed factor of Vmax Prema factor Vmax S.F. 7 6.0 2.9 1.21 0.90 2.5 8 3.0 1.6 5.00 1.08 9.4 9 15.0 9.1 1.26 1.01 2.1 10 5.0 2.6 1.17 0.99 2.3 11 10.0 3.3 1.15 0.95 3.5 14 20.0 11.9 1.47 0.95 2.5 15 7.0 1.0 1.09 0.94 7.6 17 15.0 1.7 1.12 0.99 9.9 22 7.0 3.2 0.97 0.99 2.1 23 6.0 2.2 5.00 1.05 14.0 25 6.0 2.4 1.21 1.01 3.0 27 15.0 3.5 1.25 1.05 5.4 28 6.0 1.4 1.16 1.01 5.0 30 5.0 2.5 1.13 1.01 2.3 31 5.0 1.4 1.15 0.97 4.1 32 9.0 1.1 1.25 1.05 10.2 35 10.0 3.0 1.20 0.91 4.0 36 8.0 2.8 1.41 0.99 4.0 37 5.0 2.6 1.22 0.94 2.4 39 4.0 1.2 1.51 0.94 5.0 40 5.0 1.3 1.33 0.94 5.1 44 14.0 1.7 1.03 1.10 8.5 47 17.0 6.1 1.22 1.10 3.4 48 9.0 1.1 1.43 0.90 11.7 49 14.0 12.1 4.00 0.50 4.6 THE 5.3 3.7 1.08 0.97 1.5

C20 CF: Concentration that reduces contractions of the papillary muscle by 20%.

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-15C20 Vmax: Concentration that reduces Umax by 20%, at a basic cycle length of 1000 msec.

Vmax speed factor: (% of control Vmax at a basic cycle length of 2000 msec.) / (% Of control Vmax at a basic cycle length of 500 msec.) At C20 Vmax.

Premature factor

of Vmax : (% Vmax of control in extrasystoles premature / / (% of control Vmax in normal beat) at Vmax. 5.F. : Factor of safety obtained by speed factor of Vmax x (C20 CF / C2D Vmax) TABLE II LD ₅₀ (mg / Kg) Test compound rat (i.v.) mouse (i.v. THE 17 18 Example 28 11 16 31 13 18 36 10 18

invention and then illustrated by way of examples.

A) Preparation of starting compounds:

Example I 1- (3,4-Dimethoxyphenyl) -3- / 3 '- (1,2-epoxy-3-propoxy) -phenyl _ / - 1-propanone.

100 g (0.35 mole) of 3,4-dimethoxy - ^> - 3 '-hydroxyphenylpropiophenone were heated under reflux for 23 hours with 300 ml of epichlorohydrin and 24.2 g ( 0.175 mole) of potassium carbonate, and stirred. The resulting salt was filtered and the remaining solution was evaporated under reduced pressure.

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-160 residue was recrystallized from isopropanol. Yield: 109.3 g (91.9%) of the title compound mp 81-84-C.

In the same way, the following compounds were prepared: 1- (4-Methoxyphenyl) -3- / 3 '- (1,2-epoxy-3-prapoxy) -phenyl _ / - 1-pro. panona.

1- (3,4,5-Trimethoxyphenyl) -3- / 3 '- (1,2-epoxy-3-propoxy) -phenyl _ / - 1-propanone.

1- (2,4,6-Trimethylphenyl) -3- / 3 * - (1,2-epoxy-3-propoxy) -phenyl _ / - 1-propanone.

1-pheni1-3- / 3 '- (1,2-epoxy-3-propoxy) -4'-methoxy-phenyl _ / - 1-propanone.

1- (3,4-Dimethoxyphenyl) -3- / 3 '- (1,2-epoxy-3-propoxy) -4' - methoxy-phenyl -1 / - 1-propanone.

1- (3,4,5-Trimethoxyphenyl) -3- / 3 '- (1,2-epoxy-3-propoxy) -4'-methoxy-phenyl _ / - 1-propanone.

1- (2-Metoxifer.il) -3- / 3 * - (1,2-epoxy-3-propoxy) -4 * -methoxy-phenyl J./- 1-opa nona.

1- (4-Methylphenyl) -3- / 3 '- (1,2-epoxy-3-propoxy) -4'-methoxy-phenyl _ / - 1-propanone.

1- (2,4,6-Trimethylphenyl) -3- / 3 '- (1,2-epoxy-3-propoxy) -4' -πει oxy-phenyl! / / 1-propanone.

Example II

1- (2-Naphthyl) -3- / 3 '- (1,2-epoxy-3-propoxy) -4'-methoxypheni! _ / - 1-propanone

13.1 g (0.04 mole) of 1- (2-na phyl) 1 -3- (3'-hyd roxi-4 '-met cxifen i 1) -1 were heated for 5 hours under reflux -propane, with 26.3 ml of epichlorohydrin, 90 ml of isopropanol and 1.6 g (0.04 mol) of sodium hydroxide. The resulting salt was filtered and the remaining solution was evaporated under reduced pressure. The oily residue that remained was used in the next step without being purified. Yield: 16.4 g (100 $).

Example III 1- (3-Phenanthrenyl) -3- / 3 '- (1,2-epoxy-3-propoxy) -phenyl _ / - 1-pro.

psnana

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-17 61.6 g (D, 18 moles) of 1- (3-phenanthrenyl) -3- (3'-hydroxyphenyl) -1-propanone were heated for 12 hours under reflux with 105.6 ml of epichlorohydrin, 66 ml of methanol and 7.2 g (0.18 mole) of sodium hydroxide. The resulting salt was filtered and the remaining solution was evaporated under reduced pressure. The residue was used in the next step without being purified. Production: 65.2 g (= 85.3%).

B) Preparation of the compounds of the invention:

Example I

1- (3,4-dimethoxyphenyl) -3- / 3 '- (2-hydroxy-3-terc.-pentylaminopropoxy) -phenyl _ / - 1-propanone hydrochloride

27.4 g (0.08 mole) of 1- (3,4-dimethoxyphenyl) -3- / 3 '- (1,2-epoxy-3-propoxy) -phenyl _ / - 1-propanone and 20 , 9 g (0.24 mole) of tert-pentylamine in 300 ml of methanol, and heated for 4 hours under reflux. The solvent and excess amine were removed under reduced pressure. The oily residue was recovered with methanol and concentrated hydrochloric acid was added. After heating and cooling crystals are obtained which are recrystallized from acetone. Yield: 22.8 g (61.2%) of the title compound mp - 117-1192 ° C.

In the same way the following compounds were prepared (Examples 2 to 51):

2. 1- (3,4-dimethoxyphenyl) -3- / 3 ¹ - (2-hydroxy-3-n-propylamino-propoxy) -phenyl _ / - 1-propanone hydrochloride, mp 146-147 ² C.

3. 1- (3,4-dimethoxyphenyl) -3- / 3 '- (2-hydroxy-3-morpholinopropoxy) -f en yl __ / - l OPAN pre-one, mp 148-149 C. ²

4. 1- (3,4-Dimethoxyphenyl) -3- ^ 3 '- (2-hydroxy-3-isopropylamino-propoxy) -phenyl _ / - 1-propanone hydrochloride, mp 175-177 ² C.

5. 1- (3,4-Dimethoxyphenyl) -3- / 3 '- (2-hydroxy-3-tert-butylamino-propoxy) -phenyl-1-propanone hydrochloride, m.p. 179-18 ° C.

6. 1- (3,4-Dimethoxyphenyl) -3- / 3 '- (2-hydroxy-3-pipe_ hydrochloride

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-18ridinopropoxy) -phenyl-1-propane, m.p. 141-142-C.

7. 1- (4-Methoxyphenyl) -3- / 3 '- (2-hydroxy-3-n-propylaminopropoxy) -phenyl-1-propanone hydrochloride, m.p. 128.5-129.5 20.

8. 1- (3,4,5-trimethoxyphenyl) -3- / 3 '- (2-hydroxy-3-tert.-Pentyl-aminopropoxy) -phenyl _ / - 1-propsnone hydrochloride, mp 160-161 ^S C .

9. 1- (3,4,5-trimethoxyphenyl) -3- / 3 '- (2-hydroxy-3-isopropyl-amino-propoxy) -phenyl _ / - 1-propanone hydrochloride, mp 119.5-120, 52C.

10. 1- (3,4,5-trimethoxyphenyl) -3- / 3 '- (2-hydroxy-3-tert.-butyl-aminopropoxy) -phenyl -1 / - 1-propanone hydrochloride, mp 158- 159 ⁹ C.

11. 1- (2,4,6-trimethylphenyl) -3- / 3 '- (2-hydroxy-3-tert.-Pentyl-aminopropoxy) -phenyl _ / - 1-propanone hydrochloride, mp 103-1052 Ç.

12. 1- (2,4,6-trimethylphenyl) -3- / 3 '- (2-hydroxy-3-piperidino-propoxy) -phenyl-1-propanone hydrochloride, m.p. 158-159.520.

13. 1- (2,4,6-trimethylphenyl) -3- / 3 '- (2-hydroxy-3-morpholino-propoxy) -phenyl -1 / - 1-propanone hydrochloride, mp 170-171 ² C.

14. 1- (2,4,6-trimethylphenyl) -3- / 3 '- (2-hydroxy-3-terc.-butyl-aminopropoxy) -phenyl-1-propanone hydrochloride, mp 129- 131 ^S C. 15. 1- (2,4,6-trimethylphenyl) -3- / 3 '- (2-hydroxy-3-5propylaminopropoxy) -phenyl _ / - 1-propanone semi-oxalate, mp 146-148 ² Ç.

16. 1- (2,4,6-trimethylphenyl) -3- / 3 '- (2-hydroxy-3-n-propylaminopropoxy) -phenyl _ / - 1-propanone hydrochloride, mp 84-85 ^s C.

17. 1- (2,4,6-trimethylphenyl) -3- / 3 '- (2-hydroxy-3-terc.-butylamino-propoxy) -phenyl _ / - 1-propanone hydrochloride, mp 123.5-125 , 5 ⁹ C.

15. 1-Phenyl-3- / 3 '- (2-hydroxy-3-tert-pentylarinopropoxy) -4'-me toxifenyl __ / - 1-propanone semi-oxalate, m.p. 162-164 ° C.

19. 1-Phenyl-3- / 3 '- (2-hydroxy-3-isopropylaminopropoxy) -4'-methoxyphenyl _ / - 1-propanone hydrochloride, mp 157-1582C.

20. Ethyl l-phenyl-3/3 '- (2-hydroxy-3-tert-propoxy butilamincj.) -4'-methoxyphenyl _ / - l-propanone, mp 158-159 C. ²

21. Ethyl l-phenyl-3/3 '- (2-hydroxy-3-piperidinopropoxy) -4'-methoxyphenyl _ / - l-propanone, mp 115-117 C. ^S

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-1922. 1- (3,4-dimethoxyphenyl) - 3- / l '- (2-hydroxy-3-n-propylamino-propoxy) -4' -methoxyphenyl _ / - l-propanor hydrochloride, a, mp 115-116.5

Ç.

23. 1- (3,4-dimethoxyphenyl) -3- / 3 '- (2-hydroxy-3-is-propylamino-propoxy) -4 ¹ -methoxyphenyl-1-propanone hydrochloride, mp 128131SC.

. 1- (3,4-dimethoxyphenyl) -3- / 3 '- (2-hydroxy-3-morpholino-propoxy) -4'-methoxyphenyl _ / - 1-propanone hydrochloride, m.p. 158-1612C.

25. 1- (3,4-dimethoxyphenyl) -3- / 3 '- (2-hydroxy-3-terc.-butylamino-propoxy) -4'-methoxynyl _ / - 1-propanone hydrochloride, mp 168- 170SC.

26. 1- (3,4-Dimethoxyphenyl) -3- / 3 '- (2-hydroxy-3-cyclohexylamino-propoxy) -4'-methoxyphenyl _ / - 1-propanone hydrochloride, m.p.

117.5- 120.5 ⁵ C.

27. 1- (3,4-Dimethoxyphenyl) -3- / 3 '- (2-hydroxy-3-tert-pentylamino-propoxy) -4'-methoxyphenyl _ / - 1-propanone hydrochloride, mp 147-1482C.

28. 1- (3,4,5-trimethoxyphenyl) -3- / 3 '- (2-hydroxy-3-terc.-pentylamino-propoxy) -4'-methoxyphenyl _ / - 1-propanone hydrochloride, mp 126- 1292C.

29. 1- (3,4,5-trimethoxyphenyl) -3- / 3 '- (2-hydroxy-3-n-propylamino-propoxy) -4'-methoxyphenyl-1-propanone hydrochloride, m.p.

103.5- 106 ^s C.

30. 1- (3,4,5-trimethoxyphenyl) -3- / 3 '- (2-hydroxy-3-isopropylamino-propoxy) -4 * -methoxyphenyl _ / - 1-propanone hydrochloride, m.p.

115-1162C.

31. 1- (3,4,5-trimethoxyphenyl) -3- / 3 '- (2-hydroxy-3-tert-butyl-aminopropoxy) -4'-methoxy and nil _ / - 1-propanone hydrochloride, mp 150.5-152 ² C.

32. 1- (3,4,5-trimethoxyphenyl) -3- / 3 '- (2-hydroxy-3-cyclohexyl-amino-propoxy) -4'-methoxyphenyl! _ / - 1-propa ninth hydrochloride , Federal Police. 136.5-138.52C.

33. 1- (2-Methoxyphenyl) -3- / 3 '- (2-hydroxy-3-tert. Acetate).

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-20-pentylamino-propoxy) -4'-methoxyphenyl _ / - 1-propanone, m.p. 119-120 ° C.

34. 1- (2-Methoxyphenyl) -3- / 3 '- (2-hydroxy-3-n-propylamino-propoxy) -4 ¹ -methoxyphenyl _ / - 1-propanone hydrochloride, mp 141.5143 ² C.

35. M2-methoxyphenyl) -3- / 3 '- (2-hydroxy-3-terc.-butylamino-propoxy) -4 ¹ -methoxyphenyl _ / - 1-propanone, mp 166.5 167 ⁵ C.

36. 1- (4-Methylphenyl) -3- / 3 '- (2-hydroxy-3-terc.-pentylamino-propoxy) -4' -methylphenyl __ / - 1-propanone hydrochloride, mp 107.5 - 109.52C.

37. 1- (4-Methylphenyl) -3- / 3 '- (2-hydroxy-3-n-propylamino-propoxy) -4'-methoxyphenyl _ / - 1-propanone hydrochloride, m.p. 108-1102C.

38. 1- (4-Methylphenyl) -3- / 3 '- (2-hydroxy-3-morpholinopropoxy) -4'-methoxyphenyl _ / - 1-propanone hydrochloride, mp 117-119.5 ⁵ C.

39. 1- (4-Methylphenyl) -3- / 3 ¹ - (2-hydroxy-3-terc.-butylamino-propoxy) -4'-methoxyphenyl _ / - 1-propanone hydrochloride, mp117-1192C.

40. 1- (4-Methylphenyl) -3- / 3 '- (2-hydroxy-3-piperi. Dinopropoxy) -4'-methoxyphenyl _ / - 1-propanone hydrochloride, mp 138.5-140 ² C.

41. 1- (4-Methylphenyl) -3- / 3 '- (2-hydroxy-3-cyclohexylamino-propoxy) -4'-methoxyphenyl _ / - 1-propane hydrochloride, m.p. 134-1362C.

42. 1- (2,4,6-trimethylphenyl) -3- / 3 '- (2-hydroxy-3-tert-pentyl-aminopropoxy) -4'-methoxyphenyl _ / - 1-propanone hydrochloride, mp 117- 1182C.

43. 1- (2,4,6-trimethylphenyl) -3- / 3 '- (2-hydroxy-3-piperidino-propoxy) -4 ¹ -methoxyphenyl _ / - 1-propanone hydrochloride, mp 119-1202C.

44.0 1- (2,4,6-trimethylphenyl) -3- / 3 '- (2-hydroxy-3-n-propylamino-propoxy) -4 ¹ -methoxyphenyl _ / - 1-propanone, mp 121-1222C.

45. 1- (2,4,6-trimethylphenyl) -3- / 3 '- (2-hydroxy-3-isopropylamino-propoxy) -4'-methoxyphenyl _ / - l-propanone hydrochloride,

864

X 602ΡΤ

-21p.f. 110-1119C.

46. 1- (2,4,6-timetylphenyl) -3- / 3 '- (2-hydroxy-3-morpholino-propoxy) hydrochloride 4 ¹ -methoxyphenyl _ / - 1-prapanone, mp 154-155 ⁹ C.

. 1- (2-naphthyl) -3 / 3 * - (2-hydroxy-3-tert-pentylamino-propoxy) -4'-methoxyphenyl) -1-propanone, mp 130-132 ⁹ C 48. 1- (2-naphthyl) -3- / 3 '- (2-hydroxy-3-n-propylaminopropoxy) -4 ¹ -methoxyphenyl _ / - 1-propanone, mp 142-143 ⁹ C.

. 1- (2-naphthyl) -3 / 3 '- (. 2-hydroxy-3-opropila is minopropoxi) -4'-methoxyphenyl _ / - l-propanone, mp 133-135 C. ⁹

50. 1- (3-fenantrenil) -3 / 3 '- (2-hydroxy-3-opr_o is pilaminopropoxi) -phenyl _ / - l-propanone, mp 140-142 C. ⁹

51. 1- (3-Phenanthrenyl) -3- / 3 * - (2-hydroxy-3-n-propylaminopropoxy) -phenyl_ / 1-propanone hydrochloride, mp 149-152 ⁹ C. Example 52

Tablet Manufacturing Process

a) Ingredients

Composed of Example 1 75.00 g Microcrystalline cellulose (DUST, 50 / A-m) 15.75 g Poly - (l-vinyl-2-pyrrolidone) 5.00 g Hydroxypropylmethyl cellulose 2910 3.75 g Magnesium stearate 0.50 g

100.00 g

b) Mixing and granulating compound from Example 1 and optionally sieved. All materials, except magnesium stearate, are then mixed in a mixer, where they are moistened with an appropriate amount of liquid granulation (for example, water or isopropanol-dichloromethane 1: 1). The wet mix

Z Z Λ and passed through a suitable sieve, dried in a drying chamber and sieved again. Dry and mixed granules

X 602ΡΤ

-22 with magnesium stearate in the mixer.

c) Compression of tablets. Λ

The mixture is prepared according to a) and compressed, in a tablet press, into tablets weighing from 40 to 400 mg. The compression force and the diameter of the tablet are chosen so that the disintegration time in the device. test kit according to Eur. Pharm. less than 15 minutes and for the tablets to be mechanically stable enough.

Example 53

Manufacturing process for tablets coated with a

movie THE. Ingredients The ) Tablet (see tablet manufacturing, Example 52) B ) Coating with movie

The total amount applied is 5-20% of the weight of the tablet and consists of:

Hydroxymethylcellulose 2910 77 $ (□)

Macrogol '6000 (plasticizer) 23 $

B. Preparation of the tablets (see manufacturing process for tablets, Example 52)

C. Preparation of film-coated tablets

The film coating ingredients are dissolved in a suitable solvent (for example water or ethanol / water 70:30).

The tablets are sprayed on a coating device. film coating with the solution contends the film former and the plasticizer and are dried in a stream of hot air.

The film-coated tablets are dried again in a

864

X 6Ο2ΡΤ

Υ'ί

-23 drying chamber.

Example 54

Dragee manufacturing process

A. Ingredients

a) Dragee core (see tablet manufacturing process)

b) Dragee bark

The total amount applied is 25-100% of the core weight and consists of:

5sucrose 51.4% Baby powder 24.0% Hemi-Hydrated Calcium Sulfate 10.3% Starch syrup 5.0% Arabic gum 3.9% Macrogol ^ '6000 2.9% Titanium (IV) oxide 1.6% Finely dispersed silica 0.8% Dodecyl and sodium sulfate 0.1%

100.0%

B. Preparation of the dragee cores (see tablet manufacturing process)

C. Preparation of the dragees

Composition of the dragee solution used, pre-coating composition and suspension of dragee coating.

5 dragee solution Sucrose 47.6% Starch syrup 19.1% Arabic gum 3, B% Distilled water 29.5%

100.0%

864

X 6D2PT

-24X

b) Pre-coating composition

Talc 70.0 /

Calcium sulphate hemihydrate 26.7 / Finely dispersed silica 3.3 /

100.0 /

c) Dragee coating suspension

Sucrose 47.8 / Talc 9.6 / Calcium sulphate hemihydrate 4.3 / Gum arabic 3.6 / Starch syrup 3.2 / Macrogof ^R) 6000 2.9 / Oxidodetitanium (IV) 1.6 / 5 sulfate dodecyl and sodium 0.1 / distilled water 26.4 /

100.0 /

Coating the core of the dragees.

First, the dragee cores are moistened in a rotating container containing dragee solution and then sprinkled with sufficient pre-coating compositions to roll again. After drying the cores, this process is repeated again. The cores are then dried in a drying chamber. The cores are then coated, layered with the dragee coating suspension until the desired final weight is reached. 0s

X X cores must be dried after applying each layer.

Example 55

Capsule manufacturing process A. Dosage of the active ingredient in 75 mg and more

1. Compound Ingredients of Example 2

75.00 g

Β64

X 602PT

-25 Microcrystalline cellulose (powder, 50 J / m) 16, 25 g

Poly- (l-vinyl-2-pyrrolidone) 5.00 g

Hydroxypropylmethylcellulose 2910 3.75 g

100.00 g

2. Mixing and granulation according to Example 52b)

3. Filling of the granules in the granulated capsules and placed inside hard gelatin capsules of sizes 3, 2, 1 or 0 by means of an encapsulation machine, depending on the amount placed in each capsule on the desired active ingredient dosage.

B. Dosage of the active ingredient 30-75 mg

1. Ingredients

Compound of Example 3

Microcrystalline cellulose (p o 50 y / m)

Poly- (l-vinyl-2-pyrrolidone) Hydroxypropylmethylcellulose 2910

30.00 - 75.00 g

61.25 - 16.25 g 5.00 g 3.75 g

100.00 g

The sum of the amounts of active ingredient and microscrystalline celju lose should always be 91.25 g. The amount of active ingredient is a thousand times that of a single dose.

2. Mixing and granulation according to Example 52b)

3. Filling the capsules with the granulate

100 mg of granules are placed inside each of the hard gelatin capsules, sizes 3 or 2, with the aid of an encapsulation machine.

Example 56

Ampoule manufacturing process

1. Ingredients

364 X 602ΡΤ

Compound of Example 6 1.5 g

Water for injection purposes ad: 100 ml

2. Preparation of the solution

90% of the necessary water is placed for the selected batch in a reaction vessel. The active ingredient is dissolved in said water, under heating. The final volume is obtained by adding the necessary amount to the solution after cooling.

3. Filling the ampoules with the solution in the finished solution and placed inside glass ampoules, depending on the quantity applied to the desired dosage.

The glass ampoules are then fused together.

4. Sterilization

The ampoules are steam sterilized for 20 minutes at 12 ° C ^and C.

Example 57

Suppository manufacturing process

The. Ingredients

Compound of Example 50 30 - 200 mg

Hard fat (melting point

35-36.5-C) ad: 2000 mg

B. Preparation of the Melt containing the Active Substance

The amount of hard fat needed for a specific number of suppositories is melted in a 40-C water bath. The active ingredient is pressed through a 0.8 mm sieve and mixed with the melt to give a suspension

ç. Preparation of suppositories

The melt is allowed to cool to 37-38 ^s C and placed, under agitation maintained in suppository forms in quantities such that the weight of a suppository is 2000 mg. The suppository shape is sealed after the melt solidifies.

864 X 6Q2PT

Claims (9)

1-. - Process for the preparation of non-derivatives of compounds 3- (3-hydroxyphenyl) -l-propanadine 1 I aminopropsfoz-mula ge- OH (I) and its acid addition salts, in which R and R are the same or different and represent hydrogen atoms, alkyl groups. lo, cycloalkyl, alkenyl, alkynyl or hydroxyalkyl with up to 6 carbon atoms each, alkoxyalkyl groups, alkylthio. alkyl or dialkylaminoalkyl with up to 9 carbon atoms each, or phenylalkyl or phenoxyalkyl groups having up to 6 carbon atoms in the alkyl portion, and the phenyl radical is optionally substituted by an alkyl or alkoxy group with, respectively, up to 3 carbon atoms each, or 1 2 R and R form together with the nitrogen atom that z connects them to a 5- to 7-membered saturated heterocyclic ring, z which can be optionally substituted by one or two groups, Z A * z phenyl and / or hydroxyl and contains in the ring an oxygen or nitrogen atom, as an additional hetero atom, with the additional nitrogen atom optionally substituted by an alkyl group z with 1 to 3 carbon atoms, or with a phenyl group, 3, R represents a hydrogen atom, an alkyl group Z Z Z Z with up to 3 carbon atoms, a fluorine, chlorine or bromine atom, * z z z a hydroxyl group or an alkoxy group with up to 6 carbon atoms 67 864 X 602ΡΤ -28carbon and 4 'R represents a hydrogen atom, an alkyl group with up to 3 carbon atoms, a fluorine, chlorine or XX x * bromine, or a hydroxyl or alkoxy group with up to 6 carbon atoms or R together with the phenyl group attached to it, is part of a ring aromatic system, having up to 18 carbon atoms ε n and an integer 1 to 5, characterized by the reaction of a phenolic ether of general formula II, 4 CH ₂ -CH ₂ -C0_y R W (II) O-CH ^ CH-C ^ D 3 4 in which R, and R and n have the meaning indicated for fojrrnu la I, with an amine of general formula III 1 2 HNR R 12 in which R and R have the meaning indicated for formula I and, X if appropriate, conversion of the resulting compound, with the acid, to an acid addition salt. 2-, - Process according to claim 1, carcified by NR R, in formula I, to be a tert-pentylamino, n-propylamino, 1,1-dimethylpropylamino, morpholino, isopropylamino, tert-butylamino, pyrrolidine group , piperidine or cyclohexylamine, the residue R is hydrogen or a methyl group. XX 4 * lo, methoxy or hydroxyl, R is hydrogen or a methyl, lo, methoxy, or hydroxyl group or together with the phenyl group attached to it is a 2-naphthyl group or a 3-phenanthryl group having the value 1, 2 or 3. 3-. - Process according to claim 1, 67 364 X 6D2PT -29 'ι 2 is characterized by, in formula I, NR R being a tert-ρεηtilamino, n-propylamino, isopropylamino, tert-butylamino, piperino or cyclohexylamino group, the residue R ^J being hydrogen or a' 4 methoxy group in position 4, R is a methyl or methoxyl group or R together with the phenyl group attached to it is a 2-naphthyl group having a value of 1, 2 or 3. 4-. - Process according to claim 1, characterized in that the compound prepared is 1- (3, 4.5- trimethoxyphenyl) -3- / 3 '- (2-hydroxy-3-tert-pentyl-aminopropoxy) phenyl / 1-propanone. 5-. - Process according to claim 1, characterized in that the compound prepared is l- (2, 4.6- 1-Methylphenyl1) -3- / 3 '- (2-hydroxy-3-tert-butylamino-propoxy) phenyl __ / - 1-propanone. 6-. - Process according to claim 1, characterized in that the compound prepared is 1- (3,4-dimethoxyphenyl) -3- / 3 '- (2-hydroxy-3-isopropylamino-propoxy) -4 * hydrochloride -methoxyphenyl _ / - 1-propanone. 7-. - Process according to claim 1, characterized in that the compound prepared is l- (3, 4,5-trimethoxyphenyl) -3- / 3 '- (2-hydroxy-3-cyclohexylamino-proj poxy) - 4'-methoxyphenyl __ / - 1-propanone. 8-. Process according to claim 1, caraç. characterized in that the compound prepared is 3 .- (2-naphthyl) -3- / 3 '- (2-hydroxy-3-n-propylaminopropoxy) -4'-methoxyphenyl _ / - 1-propanone hydrochloride. 9-. Process for the preparation of a pharmaceutical composition, suitable for the treatment of disorders of the cordial rhythm, characterized by combining a compound prepared according to claims 1 to 3, in an amount effective to produce an antiarrhythmic activity, with a pharmaceutical carrier.